{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T11:35:13Z","timestamp":1779363313145,"version":"3.51.4"},"reference-count":78,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T00:00:00Z","timestamp":1724112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Midwestern University Intramural funds","award":["#AZ0163"],"award-info":[{"award-number":["#AZ0163"]}]},{"name":"Midwestern University Intramural funds","award":["#AZ0226"],"award-info":[{"award-number":["#AZ0226"]}]},{"name":"Midwestern University Intramural funds","award":["#AZ21-0021"],"award-info":[{"award-number":["#AZ21-0021"]}]},{"name":"Midwestern University Intramural funds","award":["NIMHHD -U54"],"award-info":[{"award-number":["NIMHHD -U54"]}]},{"name":"Midwestern University Intramural funds","award":["#491"],"award-info":[{"award-number":["#491"]}]},{"name":"Midwestern Arizona Alzheimer\u2019s Consortium","award":["#AZ0163"],"award-info":[{"award-number":["#AZ0163"]}]},{"name":"Midwestern Arizona Alzheimer\u2019s Consortium","award":["#AZ0226"],"award-info":[{"award-number":["#AZ0226"]}]},{"name":"Midwestern Arizona Alzheimer\u2019s Consortium","award":["#AZ21-0021"],"award-info":[{"award-number":["#AZ21-0021"]}]},{"name":"Midwestern Arizona Alzheimer\u2019s Consortium","award":["NIMHHD -U54"],"award-info":[{"award-number":["NIMHHD -U54"]}]},{"name":"Midwestern Arizona Alzheimer\u2019s Consortium","award":["#491"],"award-info":[{"award-number":["#491"]}]},{"name":"RCMI BRAIN Core","award":["#AZ0163"],"award-info":[{"award-number":["#AZ0163"]}]},{"name":"RCMI BRAIN Core","award":["#AZ0226"],"award-info":[{"award-number":["#AZ0226"]}]},{"name":"RCMI BRAIN Core","award":["#AZ21-0021"],"award-info":[{"award-number":["#AZ21-0021"]}]},{"name":"RCMI BRAIN Core","award":["NIMHHD -U54"],"award-info":[{"award-number":["NIMHHD -U54"]}]},{"name":"RCMI BRAIN Core","award":["#491"],"award-info":[{"award-number":["#491"]}]},{"name":"Diabetes Action and Research Education Foundation","award":["#AZ0163"],"award-info":[{"award-number":["#AZ0163"]}]},{"name":"Diabetes Action and Research Education Foundation","award":["#AZ0226"],"award-info":[{"award-number":["#AZ0226"]}]},{"name":"Diabetes Action and Research Education Foundation","award":["#AZ21-0021"],"award-info":[{"award-number":["#AZ21-0021"]}]},{"name":"Diabetes Action and Research Education Foundation","award":["NIMHHD -U54"],"award-info":[{"award-number":["NIMHHD -U54"]}]},{"name":"Diabetes Action and Research Education Foundation","award":["#491"],"award-info":[{"award-number":["#491"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The prevalence of obesity and related consequences, including insulin resistance and Alzheimer\u2019s-like neuropathology, has increased dramatically. Contributing to this prevalence is the shift in lifestyle preference away from wholesome foods and exercise to the Western-style diet and sedentarism. Despite advances in drug development, a healthy diet and regular exercise remain the most effective approaches to mitigating the unwanted sequelae of diet-induced obesity on brain health. In this study, we used the high-fat high-sugar (HFHS) mouse model of neurodegeneration to examine the effects of exercise training (HFHS+Ex), genistein treatment (HFHS+Gen), and combination treatment (HFHS+Ex+Gen) on proteins relating to neurodegeneration in the brain of male mice. After a period of 12 weeks, as expected, HFHS feeding increased body weight, adipose tissue weight, and systemic plasma inflammation (TNF-\u03b1) compared to lean mice fed a standard diet. HFHS feeding also increased protein expression of brain markers of insulin resistance (pGSK-3\u03b2, p-IR), apoptosis (caspase 3), early neurofibrillary tangles (CP13), and amyloid-beta precursor (CT20). Compared to HFHS mice, Ex decreased body weight, plasma TNF-\u03b1, and expression of pGSK-3\u03b2, caspase 3, CP13, amyloid-\u03b2 precursor (22c11), and ADAM10. Treatment with Gen was equally protective on these markers and decreased the expression of p-IR. Combination treatment with Ex and Gen afforded the greatest overall benefits, and this group exhibited the greatest reduction in body and adipose tissue weight and all brain markers, except for 22c11 and ADAM10, which were decreased compared to mice fed an HFHS diet. In addition, levels of 4G8, which detects protein levels of amyloid-\u03b2, were decreased with combination treatment. Our results indicate that exercise training, genistein supplementation, or combination treatment provide varying degrees of neuroprotection from HFHS feeding-induced Alzheimer\u2019s pathology. Future perspectives could include evaluating moderate exercise regimens in combination with dietary supplementation with genistein in humans to determine whether the same benefits translate clinically.<\/jats:p>","DOI":"10.3390\/ijms25169019","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T09:13:48Z","timestamp":1724145228000},"page":"9019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Influence of Exercise and Genistein to Mitigate the Deleterious Effects of High-Fat High-Sugar Diet on Alzheimer\u2019s Disease-Related Markers in Male Mice"],"prefix":"10.3390","volume":"25","author":[{"given":"Juhi","family":"Shah","sequence":"first","affiliation":[{"name":"Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1138-2363","authenticated-orcid":false,"given":"Tyler","family":"Orosz","sequence":"additional","affiliation":[{"name":"Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avneet","family":"Singh","sequence":"additional","affiliation":[{"name":"Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Savan Parameshwar","family":"Laxma","sequence":"additional","affiliation":[{"name":"Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-2458","authenticated-orcid":false,"given":"Rachel E.","family":"Gross","sequence":"additional","affiliation":[{"name":"Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Smith","sequence":"additional","affiliation":[{"name":"Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Spencer","family":"Vroegop","sequence":"additional","affiliation":[{"name":"Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney","family":"Sudler","sequence":"additional","affiliation":[{"name":"Arizona College of Osteopathic Medicine, Midwestern University, 19555 N. 59th Avenue, Glendale, AZ 85308, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8122-6487","authenticated-orcid":false,"given":"James T.","family":"Porter","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce 00732, Puerto Rico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Colon","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce 00732, Puerto Rico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1341-8831","authenticated-orcid":false,"given":"Lauren","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Auburn University, Auburn, AL 36849, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeganathan 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